WO2023202582A1 - Régulateur de gpcr et son utilisation - Google Patents

Régulateur de gpcr et son utilisation Download PDF

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WO2023202582A1
WO2023202582A1 PCT/CN2023/089013 CN2023089013W WO2023202582A1 WO 2023202582 A1 WO2023202582 A1 WO 2023202582A1 CN 2023089013 W CN2023089013 W CN 2023089013W WO 2023202582 A1 WO2023202582 A1 WO 2023202582A1
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membered
nmr
group
alkyl
methyl
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PCT/CN2023/089013
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Chinese (zh)
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焦宁
孙金鹏
于晓
豆晓东
徐国峰
程杰
霍童雨
高明新
赵心怡
王佳乐
张才方
刘雅萌
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北京昌平实验室
北京大学
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to compounds that act as modulators of GPR132, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms.
  • the present invention also relates to methods for the preparation and pharmaceutical uses of said compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms.
  • G protein-coupled receptors are a type of transmembrane protein that transmit chemical signals from extracellular matrix proteins to intracellular cells and participate in and regulate the operation of physiological and pathological functions. More than 800 GPCRs have been identified in the human genome and are divided into categories A, B, C, and F based on amino acid sequence similarity. Among them, class A (also called rhodopsin-like GPCR) family members are the largest and consist of 719 GPCRs.
  • GPCR signal regulation involves ligands, GPCRs, effector proteins and corresponding downstream signaling pathways. After the ligand acts on the GPCR, the GPCR is activated and undergoes conformational rearrangement, recruiting effector proteins and exerting its signaling function. GPCR signaling has a high degree of biological complexity and importance, making GPCRs a valuable drug target.
  • G protein-coupled receptor 132 is a seven-fold transmembrane G protein-coupled receptor that belongs to the rhodopsin family (Class A) GPCR.
  • B cells and T cells could upregulate the expression of GPR132 under stress induction, causing cell cycle arrest in the G2 phase. Therefore, they named the gene encoding this protein G2A (G2 accumulation) and considered it to be a potential inhibitor.
  • GPR132 expression is tissue-specific and cell-type specific, and mainly exists in blood and lymphoid tissues. GPR132 expression is mainly found in blood cells such as macrophages, dendritic cells, neutrophils, T cells, and B lymphocytes, but its expression in immune cells is not specific.
  • GPR132 mainly plays a role in immune cells, regulates immune function, and is closely related to a variety of immune-related diseases and malignant tumors.
  • Le et al. found that GPR132-deficient mice developed delayed autoimmune syndrome and proposed that GPR132 is a potential target for autoimmune diseases.
  • Parks et al. found that GPR132 deletion improved atherosclerosis in low-density lipoprotein receptor-deficient mice.
  • Tabea et al. found that GPR132 deficiency reduces the number of immune cells at the nerve injury site and reduces the release of pro-inflammatory cytokines, thereby reducing the inflammatory response. Therefore, inhibiting GPR132 is expected to be applied to the relief and treatment of neural pain.
  • GPR132 may play an important role in the tumor microenvironment. Chen et al. found that in a mouse breast cancer model, GPR132 deficiency prevented macrophages from polarizing to the M2 type, thereby hindering the invasion and metastasis of tumor cells and inhibiting tumor lung metastasis.
  • the inventor of the present application has obtained a class of benzofuran derivatives, which can serve as GPR132 modulators (such as antagonists) and can be used to prevent or treat GPR132-related diseases, such as arterial disease.
  • GPR132 modulators such as antagonists
  • GPR132-related diseases such as arterial disease.
  • Atherosclerosis, neuropathic pain, breast cancer, hyperlipidemia, type 2 diabetes, etc. thereby providing the following invention.
  • the present invention provides compounds represented by formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolites form,
  • A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo3 Any _ _ _ _ _
  • the 6- to 10-membered aryl group, the 5- to 14-membered heteroaryl group, the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclyl group, and the benzo 3- to 6-membered cycloalkyl group are substituted by one or more M replaced;
  • R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • Q is phenyl or benzo 5-6 membered heteroaryl ring
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is replaced by one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • R 7 and R 8 are each independently selected from C 1 -C 6 alkyl, and q is selected from an integer between 1 and 10;
  • L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium, carbonyl; and, the compound is not 3-methyl Base-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
  • A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo 3 to 6 membered cycloalkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 14 membered heteroaryl group, 3 to 6 membered cycloalkyl group, 3 to 6 membered aryl group Heterocyclyl, benzo 3 to 6-membered cycloalkyl is substituted by one or more M, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkane Base, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 1 -C 6 haloalkyl group, C 1
  • R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • Q is phenyl or benzo 5-6 membered heteroaryl ring
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ; R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium;
  • the compound is not 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
  • A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6
  • cycloalkyl benzo 5- to 6-membered heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 cycloalkenyl , the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group, 8 to 14 membered condensed heteroaryl group, 5 to 6 membered cycloalkyl group, 5 to 6 membered heterocyclyl group, benzo 5 to 6 membered
  • the ring alkyl group is substituted by one or more M;
  • R 7 and R 8 are each methyl, and q is selected from an integer between 1 and 4;
  • A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing condensed heteroaryl group (such as a benzo 5- to 6-membered oxygen-containing heteroaryl group).
  • A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, indolyl, cyclohexenyl, benzocyclohexanyl; optionally, the phenyl, naphthalene base, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl
  • halogen eg fluorine, chlorine, bromine, iodine
  • C 1 -C 4 alkyl trifluoromethyl, methoxy,
  • A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocycle base, benzo 5 to 6 membered cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group , 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6 membered cycloalkyl substituted by one or more M.
  • M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
  • R 3 and R 4 are each independently selected from hydrogen and hydroxyl.
  • the C 1 -C 6 alkoxy group is substituted with one or more groups selected from: C 1 -C 6 fluoroalkyl, cyclopropyl.
  • A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing fused heteroaryl group, and a 5- to 6-membered cycloalkyl group.
  • M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
  • A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuryl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl; optionally, the phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl A group is substituted with one or more M's.
  • M is selected from the group consisting of: halogen (e.g., fluorine, chlorine, bromine), cyano, -NHCH 3 , C 1 - C 4 alkyl, C 2 -C 4 alkynyl, trifluoromethyl, methoxy, ethoxy, acetyl, phenyl, phenoxy.
  • halogen e.g., fluorine, chlorine, bromine
  • cyano e.g., cyano, -NHCH 3 , C 1 - C 4 alkyl, C 2 -C 4 alkynyl, trifluoromethyl, methoxy, ethoxy, acetyl, phenyl, phenoxy.
  • the methoxy or ethoxy group is substituted with one or more trifluoromethyl or cyclopropyl groups.
  • R1 is hydroxyl or -NHOH.
  • R 2 halo is selected from C 1 -C 6 alkyl (eg, methyl), C 1 -C 6 haloalkyl (eg, fluoromethyl).
  • L 1 is absent or selected from -(CH 2 ) n -, cyclopropyl, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is methyl Substituted or deuterated; optionally, -( CH2 ) n- is substituted or deuterated by methyl or carbonyl.
  • L 2 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with methyl or deuterated generation.
  • the 5-6 membered heteroaryl group is selected from the group consisting of furyl, thienyl, and pyrrolyl. In certain embodiments, the 5-6 membered heteroaryl group is furyl.
  • the compound has a structure represented by Formula (II):
  • X is selected from O, S or NH.
  • the compound has a structure represented by Formula (III) or (IV):
  • X is O.
  • X is S.
  • X is NH
  • A is phenyl optionally substituted with one or more M, M as defined above.
  • the compounds of the invention are selected from the compounds shown in Table 1:
  • the compound has a structure represented by Formula (V):
  • Core is X is selected from O, S or NH,
  • R2 is as defined above.
  • R2 is selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), C 1 -C 6 alkyl (e.g., methyl).
  • halogen e.g., fluorine, chlorine, bromine
  • C 1 -C 6 alkyl e.g., methyl
  • Core is selected from:
  • the compound is selected from the compounds shown in Table 2:
  • the compound has a structure represented by Formula (VI):
  • A is as defined above.
  • A is selected from phenyl optionally substituted with one or more M selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl Oxygen group, nitro group, hydroxyl group, -NR 3 R 4 , R 3 and R 4 are each independently selected from hydrogen and C 1 -C 6 alkyl group.
  • the compound is selected from the compounds shown in Table 3:
  • M is selected from: halogen, C 2
  • the compound is selected from the compounds shown in Table 4:
  • the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted with one or more M: phenyl, naphthyl, benzo 5 to 6 Membered heterocyclyl (such as benzo 5- to 6-membered oxygen-containing heterocyclyl), benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl); M is selected from halogen , C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • the compound is selected from the compounds shown in Table 5:
  • the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted by one or more M: C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 membered cycloalkyl, 5 to 6 membered cycloalkenyl, 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl; M is selected from C 1 -C 6 alkyl, halogen.
  • the compound is selected from the compounds shown in Table 6:
  • the structure of the compound of the invention is represented by Formula (VII),
  • A is selected from phenyl, naphthyl, L 1 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with one or more groups selected from: halogen, C 1 -C 6 alkyl, carbonyl.
  • the compound is selected from the compounds shown in Table 7:
  • the structure of the compound of the invention is as shown in formula (VII), wherein L 1 is absent and A is selected from the following groups optionally substituted by one or more M: phenyl, naphthyl, Benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl), benzo 5- to 6-membered cycloalkyl, M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membered heterocyclyl, R 3 and R 4 are each independently selected from C 1 -C 6 alkyl, the 5 to 6-membered heterocyclic group Heterocyclyl is optionally substituted with C 1 -C 6 alkyl.
  • M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membere
  • the compound is selected from the compounds shown in Table 8:
  • the pharmaceutically acceptable ester of the compound of the present invention is preferably ethyl carboxylate.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), which is pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms; optionally, the pharmaceutical composition also includes a pharmaceutically acceptable carrier or excipient agent.
  • the pharmaceutical composition may be in any form known in the medical field.
  • the pharmaceutical composition can be tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, lozenges, suppositories, injections (including injections, lyophilized powder), inhalants, sprays, etc.
  • the preferred dosage form depends on the intended mode of administration and therapeutic use.
  • the compounds, pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and metabolite forms thereof may be in unit dosage form Present in pharmaceutical compositions to facilitate administration.
  • the compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or the pharmaceutical compositions may be prepared by those skilled in the art. Administration may be carried out by any suitable method known, including, but not limited to, oral, rectal, parenteral or topical administration.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like.
  • Liquid dosage forms may contain, in addition to the active compound, inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers. Besides inert diluents, liquid dosage forms for oral administration can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, lozenges, powders, granules, etc.
  • solid dosage forms may contain pharmaceutically acceptable inert excipients or carriers, such as fillers, binders, wetting agents, disintegrating agents, lubricants, and mixtures thereof.
  • the compounds or pharmaceutical compositions of the invention may also be administered parenterally.
  • parenteral administration for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion.
  • Dosage forms for parenteral administration may be injectable preparations, including injectable solutions, sterile powders for injection, or concentrated solutions for injection.
  • injection dosage forms may contain pharmaceutically acceptable carriers such as sterile water, Ringer's solution and isotonic sodium chloride solution, and may also add appropriate additives such as antioxidants, buffers and Bacteriostat.
  • Topical administration such as transdermal administration (eg, via a transdermal patch or iontophoretic device), intraocular administration, or intranasal or inhaled administration.
  • Dosage forms for transdermal administration may be topical gels, sprays, ointments and creams. Topical dosage forms may contain, in addition to the active compound, ingredients that enhance absorption or penetration of the active compound through the skin or other area of action.
  • administration will be accomplished using patches of the storage and porous film type or solid matrix variety.
  • Dosage forms for topical administration to the eye may be eye drops in which the compound of the invention is dissolved or suspended in a suitable carrier.
  • the compounds of the present invention are conveniently delivered as solutions or suspensions from pressure spray containers by patient compression or pumping, or It is delivered as an aerosol spray formulation from a pressure container or nebulizer using a suitable propellant.
  • Dosage forms for rectal administration may be suppositories.
  • compositions of the present invention can be prepared by any known pharmaceutical process, such as effective formulation and administration methods.
  • effective formulations and methods of administration are well known in the art and are described in standard textbooks.
  • Formulations of drugs are described in, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and edited by Kibbe et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.
  • the pharmaceutical composition contains a compound of the invention, a pharmaceutically acceptable salt or ester, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form thereof, or a metabolite thereof
  • the amount of the form is 0.01-2000 mg, preferably 0.1-1000 mg, more preferably 1-800 mg, more preferably 10-600 mg, particularly preferably 50-500 mg.
  • the pharmaceutical composition of the present invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of a compound as described herein, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate substances, crystal forms, and their metabolite forms.
  • “Prophylactically effective amount” refers to an amount sufficient to prevent, prevent, or delay the occurrence of disease.
  • a “therapeutically effective amount” means an amount sufficient to cure or at least partially prevent disease and its complications in a patient who is already suffering from the disease.
  • therapeutically effective amounts of compounds as described herein, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and their metabolite forms It may vary based on factors such as the severity of the disease being treated, the overall status of the patient's own immune system, the patient's general condition such as age, weight, and gender, the manner in which the drug is administered, and other treatments being administered at the same time, etc.
  • the dosing regimen can be adjusted to obtain the optimal desired response (eg, therapeutic or prophylactic response).
  • the dose may be administered as a single dose, may be administered multiple times over a period of time, or may be proportionally reduced or increased according to the exigencies of the treatment situation.
  • Typical non-limiting ranges for therapeutically or prophylactically effective amounts of the compounds of the invention, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms are 0.01 ⁇ 1000mg/kg, such as 0.1 ⁇ 500mg/kg. It should be noted that dosage may vary depending on the type and severity of symptoms requiring treatment. In addition, those skilled in the art understand that for any particular patient, the specific dosage regimen should be adjusted over time based on the needs of the patient and the professional evaluation of the physician; the dosage ranges given here are for illustrative purposes only and are not limiting. Use or scope of the pharmaceutical composition of the present invention.
  • the pharmaceutical compositions may also include additional pharmaceutically active agents.
  • the compound of the invention and the additional pharmaceutically active agent are provided as separate or mixed components in the pharmaceutical composition.
  • the compounds of the invention and the additional pharmaceutically active agent may be administered simultaneously, separately or sequentially.
  • the compounds of the present invention can be used as modulators (eg antagonists) of GPR132 to prevent or treat diseases related to GPR132.
  • the application provides the use of a compound for the preparation of a medicament for preventing or treating diseases related to GPR132, the compound being selected from the group consisting of compounds of formula (I) or the following table, Its pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms
  • the disease associated with GPR132 is selected from the group consisting of tumors, metabolic diseases, immune-related diseases, and neuropathic pain.
  • the tumor is selected from the group consisting of: breast cancer, melanoma, meningioma, soft tissue sarcoma, Salivary gland tumors, primary liver cancer, intraspinal tumors, mediastinal tumors, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumors, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma , pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, stomach cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulva Cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanom
  • the metabolic disease is selected from atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver disease or non-alcoholic steatohepatitis (NASH)), metabolic syndrome syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., , complications of diabetes, such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension, stroke).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • metabolic syndrome syndrome type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., , complications of diabetes, such
  • the immune-related disease is selected from:
  • Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes, essential thrombocytopenic purpura, autoimmune hemolytic anemia, ulcerative colitis, skin diseases, chronic liver disease .
  • the invention provides a method for preventing or treating a disease associated with GPR132 in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or metabolite forms thereof selected from compounds of formula (I) or the following table
  • the disease associated with GPR132 may be selected from the diseases described above.
  • the application also provides the synthesis of compounds of formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms
  • the method includes the following steps: reacting compounds of general formula (IA) and general formula (IB) in the presence of inorganic bases or organic bases to obtain compounds of general formula (I):
  • the organic base is preferably selected from triethylamine and diisopropylethylamine; the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
  • the present invention also provides a method for preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which method includes the following steps: in the presence of an inorganic base or an organic base, the general formula (II-A) React with the compound of general formula (II-B) to obtain the compound of general formula (I):
  • rings A, L 1 , L 2 and R 1 -R 6 are as mentioned above respectively;
  • the inorganic base is preferably selected from potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide and cesium carbonate;
  • the organic base is preferably selected from triethylamine and diisopropylethylamine;
  • the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
  • C 1 -C 6 alkyl refers to a group obtained by removing one hydrogen atom from a straight or branched chain alkane containing 1 to 6 carbon atoms, preferably C 1 -C 6
  • the alkyl group is a C 1 -C 4 alkyl group, and specific examples thereof include but are not limited to: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl or isobutyl .
  • C 2 -C 6 alkenyl refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2 to 6 carbon atoms. Examples include but Not limited to: vinyl, 1-propen-1-yl, allyl, 1-buten-1-yl, 1-penten-1-yl, 1,3-butadien-1-yl, 1, 4-Pentadien-1-yl. Preferred C 2 -C 6 alkenyl groups are C 2 -C 4 alkenyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched chain alkynyl group with 2 to 6 carbon atoms containing at least one triple bond. Examples include but are not limited to: acetylene base, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl Base-2-hexynyl. Preferred C 2 -C 6 alkynyl groups are C 2 -C 4 alkynyl groups.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • halogenated means that a hydrogen on a group or compound is replaced by one or more halogen atoms, including fully halogenated and partially halogenated.
  • alkoxy refers to a group formed in the alkyl-O- manner, examples include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, or n-hexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The ring of the cycloalkyl group may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, including Containing 3 to 20 ring atoms, one or more (eg 1, 2, 3 or 4) of the ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 10 ring atoms; most preferably it contains 5 to 6 ring atoms, of which 1 to 2 are selected from nitrogen, oxygen or Sulfur heteroatoms.
  • the sulfur atoms may be oxosubstituted.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably 6 -10 yuan, such as phenyl, naphthyl.
  • heteroaryl refers to a heteroatom-containing monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably from 5 to 10-membered heteroaryl groups include 5- to 8-membered monocyclic heteroaryl groups and 8- to 14-membered fused heteroaryl groups.
  • the term "5- to 8-membered monocyclic heteroaryl” refers to an aromatic monocyclic cyclic group containing 5 to 8 ring atoms, at least one of which is a heteroatom, e.g. Nitrogen atom, oxygen atom or sulfur atom, including the case where the carbon atom, nitrogen atom and sulfur atom on the ring are substituted by oxygen.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxanyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, Py
  • the term "8- to 14-membered fused heteroaryl” refers to a group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other. , an unsaturated aromatic cyclic structure, in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom, and also includes the case where the carbon atoms, nitrogen atoms and sulfur atoms on the ring are oxo-substituted.
  • Examples include, but are not limited to: benzofuryl, benzisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl , quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazoline base, quinoxalinyl, phenolazine, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, etc.
  • substituted means that one or more hydrogen atoms on a group are replaced by one or more substituents, which may be the same or different.
  • C2 alkyl is substituted means that one or more hydrogen atoms on the C2 alkyl group are replaced by one or more substituents.
  • the term "pharmaceutically acceptable salt” refers to (i) the acidic functional group (such as -COOH) present in the compound provided by the invention and the appropriate inorganic or organic cation (base) formed Salts, and include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, etc.
  • alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.
  • alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, etc.
  • inorganic alkali salts such as ammonium salt
  • organic alkali salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroplutide Caine salt, procaine salt, diethanolamine salt, N-benzyl-phenylethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt.
  • the term "pharmaceutically acceptable ester” refers to the ester of -COOH present in the compounds provided by the present invention with an appropriate alcohol (such as methanol or ethanol), or the ester provided by the present invention.
  • the -OH present in the compound forms an ester with a suitable acid (for example, a carboxylic acid or an oxygenated inorganic acid).
  • suitable ester groups include but Without limitation, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate or palmitate. Esters can undergo hydrolysis reactions in the presence of acids or bases to generate corresponding acids or alcohols.
  • solvate refers to a substance formed by the association of a compound of the invention with a solvent molecule.
  • the solvent can be an organic solvent (such as methanol, ethanol, propanol, acetonitrile, etc.).
  • the compound of the present invention can form an ethanolate with ethanol.
  • the compounds of the present invention can also form hydrates with water.
  • the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of substances, due to the influence of various factors, the bonding methods within or between molecules change, resulting in different arrangements of molecules or atoms in the crystal lattice space, forming different crystal structures.
  • the compound of the present invention can exist in one crystal structure or in multiple crystal structures, that is, it has "polymorphic form".
  • the compounds of the invention may exist in different crystalline forms.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above.
  • a compound of the present invention contains an olefinic double bond, it includes both cis and trans isomers, as well as any combination thereof, unless otherwise stated.
  • prodrug refers to a compound of the present invention that can be converted in a subject through reactions such as oxidation, reduction, hydrolysis, and the like.
  • the prodrug itself may or may not have the biological activity of the compound of formula (I) (eg, regulating glucose and lipid metabolism activity, anti-inflammatory activity, antioxidant activity).
  • compounds of formula (I) containing hydroxyl or carboxyl groups may be administered in the form of esters, which are hydrolytically converted in vivo to hydroxyl or carboxyl compounds.
  • compounds of formula (I) including amino groups are acylated, alkylated or phosphorylated to form compounds such as eicosanoylamino, alanylamido, pivaloyloxymethylamino and are administered .
  • prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • prodrugs according to the present invention include: (i) if the compound of formula (I) contains a carboxylic acid function (-COOH), then its esters are included, for example, a (C 1 -C 8 ) alkyl group is substituted for the hydrogen; ( ii) if the compound of formula (I) contains an alcohol functional group (-OH), its ethers are included, for example, (C 1 -C 6 )alkanoyloxymethyl is used instead of hydrogen; and (iii) if the compound of formula (I) Amides containing primary or secondary amino functional groups (-NH 2 or -NHR, where R is not H) include, for example, a (C 1 -C 10 ) alkanoyl group in place of one or two hydrogens. In addition, certain compounds of formula (I) may themselves serve as prodrugs for other compounds of formula (I).
  • the term "pharmaceutically acceptable carrier or excipient” refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed.
  • disintegrants include, but are not limited to: disintegrants, binders, surfactants, glidants , lubricants, pH adjusters, ionic strength enhancers, reagents to maintain osmotic pressure, reagents to delay absorption, diluents, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, etc.
  • the term "subject" refers to a mammal, such as a rat, rabbit, dog, such as a primate mammal, such as a monkey, human.
  • modulator refers to a molecule that can interact directly or indirectly with a target.
  • modulators include, but are not limited to, agonists, partial agonists, inverse agonists, and antagonists.
  • the modulator is an agonist.
  • agonist refers to a molecule that binds to a specific receptor and triggers a response in a cell.
  • Agonists can mimic the effects of endogenous ligands such as LPA, prostaglandins, hormones or neurotransmitters that bind to the same receptor.
  • Antagonist refers to a molecule that attenuates, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, noncompetitive antagonists, noncompetitive antagonists, partial agonists, and inverse agonists.
  • Step 2 3-Methyl-5-(chlorosulfonyl)benzofuran-2-carboxylic acid ethyl ester
  • Step 3 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate ethyl ester
  • the preparation method was the same as Example 1, except that 4-(2-aminoethyl)tetrahydropyran was used instead of phenylethylamine to prepare the title compound. 0.35g of white solid was obtained, with a yield of 89%.
  • the preparation method was the same as Example 1, except that (1R,2S)-2-phenyl-cyclopropylamine was used instead of phenylethylamine to prepare the title compound. 147 mg of white solid was obtained, with a yield of 99%.
  • the preparation method was the same as Example 1, except that 2-([1,1'-biphenyl]-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound. 0.39g of white solid was obtained, with a yield of 43%.
  • the preparation method was the same as Example 1, except that 2-(benzofuran-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound.
  • Step 4 3-Methyl-5-((2-phenylethyl)sulfonamido)benzofuran-2-carboxylic acid ethyl ester
  • the preparation method is the same as in Example 19, except that benzyl sulfonyl chloride is used instead of 2-phenyl-ethanesulfonyl chloride to obtain the title compound compound. 80 mg of light pink solid was obtained, with a yield of 30.3%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(4-phenylbutylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 164 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(4-phenylbut-2-yl)sulfamoyl)benzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 165 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-cyclohexylethyl)sulfamoyl)benzofuran-
  • the title compound was obtained by substituting ethyl 2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 168 mg of white solid was obtained, with a yield of 85%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(but-3-yn-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 147 mg of white solid was obtained, with a yield of 88%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(but-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 103 mg of white solid was obtained, with a yield of 80.5%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)sulfamoyl)benzofuran-2 is used -Ethyl carboxylate was substituted for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate to give the title compound. 161 mg of white solid was obtained, with a yield of 81%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(thiophen-2-yl)ethyl)sulfamoyl)benzene is used
  • the title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 146 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(2-(pyridin-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate is used instead 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 172 mg of white solid was obtained, with a yield of 88%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2,3-dihydro-1H-inden-2-yl)sulfamoyl)benzofuran-2-carboxylic acid is used
  • the title compound was obtained by substituting ethyl ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 127 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(1-naphthyethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl-5- (N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 216 mg of white solid was obtained, with a yield of 83%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-((1R,2S)-2-phenylcyclopropyl)sulfamoyl)benzene is used
  • the title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 75 mg of white solid was obtained, with a yield of 57.7%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(4-fluorophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 115 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(4-chlorophenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 116 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromopheneethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 148 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromophenylethyl)sulfamoyl)benzofuran-2-
  • the title compound was obtained by substituting ethyl carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-methoxyphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl Ethyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used to prepare the title compound. 188 mg of white solid was obtained, with a yield of 89%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(3-methylphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 249 mg of white solid was obtained, with a yield of 97%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 102 mg of white solid was obtained, with a yield of 92%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 181 mg of white solid was obtained, with a yield of 87%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzo Furan-2-carboxylic acid ethyl ester was substituted for 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 216 mg of pink solid was obtained, with a yield of 91%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(2-(benzofuran-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used.
  • the title compound was obtained by substituting the ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
  • the preparation method is the same as Example 25, except that 3-methyl-5-((2-phenylethyl)sulfonamide)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 68 mg of light yellow solid was obtained, with a yield of 69%.
  • Example 25 According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-6-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, and the other conditions were the same. 38 mg of white solid was obtained, with a yield of 74%.
  • Example 25 According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(3-(1-methyl-1H-pyrazol-4-yl)phenylethyl)sulfamoyl) Benzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. 41 mg of yellow solid was obtained, with a yield of 41%.

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Abstract

L'invention concerne un composé d'un régulateur de GPR132, un sel ou ester pharmaceutiquement acceptable, un promédicament, un stéréoisomère, un hydrate, un solvate, une forme cristalline ou une forme métabolite de celui-ci, ainsi qu'un procédé de préparation et une utilisation médicinale associés.
PCT/CN2023/089013 2022-04-18 2023-04-18 Régulateur de gpcr et son utilisation WO2023202582A1 (fr)

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CN105085450A (zh) * 2015-09-14 2015-11-25 中国药科大学 苯并呋喃类衍生物、其制备方法及其治疗作用
CN109705071A (zh) * 2017-10-25 2019-05-03 成都先导药物开发有限公司 Hdac抑制剂及其制备方法和用途
US20210095293A1 (en) * 2016-05-05 2021-04-01 The Board Of Regents Of The University Of Texas System Methods of treating cancers with gpr132 inhibitors
CN115215823A (zh) * 2021-04-16 2022-10-21 青岛睿吉医疗技术有限公司 Fxr调节剂及其制备方法、药物组合物和用途

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US20130059858A1 (en) * 2010-05-06 2013-03-07 Bristol-Myers Squibb Company Benzofuranyl analogues as gpr119 modulators
CN105085450A (zh) * 2015-09-14 2015-11-25 中国药科大学 苯并呋喃类衍生物、其制备方法及其治疗作用
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CN109705071A (zh) * 2017-10-25 2019-05-03 成都先导药物开发有限公司 Hdac抑制剂及其制备方法和用途
CN115215823A (zh) * 2021-04-16 2022-10-21 青岛睿吉医疗技术有限公司 Fxr调节剂及其制备方法、药物组合物和用途

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